Substituted isoquinoline derivatives and their use as anticonvulsants

ABSTRACT

The present invention relates to substituted isoquinoline derivatives and their use as anticonvulsants.

This is a 371 of International Application PCT/GB98/03785, filed Dec.16, 1998, which claims benefit from the following ProvisionalApplication: GB 97256695.1, filed Dec. 17, 1997.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents.

U.S. Pat. No. 4,022,900 (Marion) disclosesbenzamido-etrahydroisoquinolines having anti-hypertensive andvasodilator properties.

WO97/48683 (SmithKline Beecham) discloses that benzamide compounds offormula (A) below possess anticonvulsant activity and are thereforebelieved to be useful in the treatment and/or prevention of anxiety,mania, and related depression disorders.

where n and p are independently integers from 1 to 4 and (n+p) is from 2to 5;

R¹ is C₁₋₆allylO—;

R² is hydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃, CF₃O—,CF₃S—, CF₃CO—, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl-,C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂— or(C₁₋₄alkyl)NHSO₂—;

R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl,C₁₋₆alkylO—, C₁₋₆alkylS—, C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃CO—,C₁₋₆alkylCO—, C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, or —NR⁵R⁶ where R⁵ ishydrogen or C₁₋₄alkyl, and

R⁶ is hydrogen, C₁₋₄alkyl, —CHO, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

R⁴ is hydrogen, C₁₋₆alkyl, C₁₋₆alkenyl, or C₁₋₆alkynyl;

and also the compounds:N-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide,N-7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide,N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide,N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide,N-(5-iodo-1,2,3,4tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinyl-benzamide,N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazirinyl-benzamideandN-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide.

It has now been surprisingly found thattetrahydroisoquinolinyl-carboxamide compounds of formula (I) belowpossess anti-convulsant activity and are believed to be useful in thefor the treatment and/or prophylaxis of anxiety, mania, depression,panic disorders and/or aggression, disorders associated with asubarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from substances of abuse such as cocaine, nicotine, alcoholand benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, multiple sclerosis (MS) and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS).

Accordingly, the present invention provides a compound of formula (I) orpharmaceutically acceptable salt thereof:

where Q is a monocyclic or bicyclic aryl or heteroaryl ring,

R¹ is hydrogen, C₁₋₆alkyl (optionally substituted by hydroxy orC₁₋₄alkoxy), C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— orC₁₋₆alkylSO₂—,

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O, CF₃S—, CF₃CO—, tifluoromethyldiazirinyl, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO, CONH₂, CF₃SO₂,C₁₋₆alkenyl, C₁₋₆alkynyl or C₁₋₆hydroxyalkyl; or —NR³R⁴ where R³ ishydrogen or C₁₋₄alkyl, and

R⁴ is hydrogen, C₁₋₄alkyl, formyl, —CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or twoR² groups together form a carbocyclic ring that is saturated orunsaturated and unsubstituted or substituted by —OH or ═O; and

X is halogen, C₁₋₆alkoxy, C₁₋₆alkyl, C₂₋₆alkenyl optionally substitutedby phenyl.

When compounds of the present invention possess chiral centres and assuch may exist in different enantiomeric forms, the present inventionextends to each enantiomeric form and mixtures thereof includingdiastereoisomers and racemates. Alkenyl compounds exist as geometricisomers and the present invention extends to each isomeric form andmixtures thereof.

The ring system Q is typically optionally substituted phenyl oroptionally substituted thiophenyl. When two R² groups form a carbocyclicring, this is typically a 5-7 membered ring, so that Q may be anaphthalene or an indane or indanone ring system.

In the formula (I), alkyl groups, including alkyl groups that are partof other moieties, such as alkoxy or acyl, may be straight chain orbranched. Phenyl groups, including phenyl groups that are part of othermoieties, in R² may optionally be substituted with one or moreindependently selected halogen or C₁₋₆alkyl, C₁₋₆alkoxy orC₁₋₆alkylcarbonyl. Suitable C₃₋₆cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituentsinclude fluoro, chloro, iodo and bromo.

One suitable group of compounds of this invention are of formula (IA)

and another suitable group are of formula (IB)

A suitable group of compounds of formula (I) have

R¹ as hydrogen, methyl, ethyl, propyl, hydroxyethyl, formyl, acetyl,trifluoroacetyl or methanesulfonyl,

R² as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl,t-butyl, phenyl, methoxy, ethoxy, isopropoxy, n-butoxy,cyclopropylmethoxy, phenoxy, benzyloxy, amino, acetylamino, nitro,azido, cyano, bromo, chloro, fluoro, iodo, acetyl, propionyl, pivaloyl,iso-butyroyl, benzoyl, iodobenzoyl, tifluoromethyl, perfluoroethyl,trifluoromethoxy, trifluoroacetyl, trifluoromethyldiazirinyl,methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl,CF₃SO₂;

or two groups R² form a benzene, cyclopentane or cyclopentanone ring;

X as methyl, ethyl, chloro, bromo, iodo, fluoro, phenylethenyl.

A preferred group of compounds of formula (I) have

R¹ as hydrogen, methyl, hydroxyethyl, formyl or trifluoroacetyl.

R² as hydrogen or one or more of methyl, ethyl, iso-propyl, methoxy,ethoxy, isopropoxy, acetyl, propionyl, pivaloyl, cyano, bromo, chloro,fluoro, iodo, trifluoromethyl.

X as methyl, ethyl, chloro or bromo.

In a special class of compounds of formula (I), suitable for use asmechanistic probes, R² groups are photolabile groups, such as N₃,benzoyl and trifluoromethyldiazirinyl. Also radiolabels such as ¹²⁵I canbe incorporated at R, and ³H can be located at suitable positions.

Examples of compounds of formula (I) are:

N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2-(2-Hydroxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2-formyl-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-chloro-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Styryl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Styryl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Styryl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamidehydrochloride

N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

N-(8-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide.

When synthesised, these compounds are often in salt form, such as thehydrochloride or trifluoroacetate, and such salts also form part of thisinvention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

The above compounds and pharmaceutically acceptable salts thereof,especially the hydrochloride, and pharmaceutically acceptable solvates,especially hydrates, form a preferred aspect of the present invention.

The administration of such compounds to a mammal may be by way of oral,parenteral, sub-lingual, nasal, rectal, topical or transdermaladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral,including sublingual, rectal, topical or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colorants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art. Suitable fillers for useinclude cellulose, mannitol, lactose and other similar agents. Suitabledisintegrants include starch, polyvinylpyrrolidone and starchderivatives such as sodium starch glycollate. Suitable lubricantsinclude, for example, magnesium stearate. Suitable pharmaceuticallyacceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. Oral formulationsalso include conventional sustained release formulations, such astablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Accordingly, the present invention further provides a pharmaceuticalcomposition for use in the treatment and/or prophylaxis of anxiety,mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, multiple sclerosis (MS)and motor neurone disease, ataxias, muscular rigidity (spasticity),temporomandibular joint dysfunction, or amyotrophic lateral sclerosis(ALS) which comprises a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, oramyotrophic lateral sclerosis (ALS) comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof.

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the manufacture of a medicament for the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes,multiple sclerosis (MS) and motor neurone disease, ataxias, muscularrigidity (spasticity), temporomandibular joint dysfunction, oramyotrophic lateral sclerosis (ALS).

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, multiple sclerosis (MS) and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, oramyotrophic lateral sclerosis (ALS).

Another aspect of the invention is a process for the preparation ofcompounds of formula (I), which comprises reacting a compound of formula(II)

where R^(1A) is R¹ as defined for formula (I) or a group convertible toR¹ and X^(A) is X as defined in claim 1 or a group convertible to X witha compound of formula (III)

where Q is as defined in formula (I), Y is Cl or OH, and R^(2A) groupsare independently R² as defined for formula (I) or groups convertible toR², and where required converting an X^(A), R^(1A) or R^(2A) group to anX, R¹ or R² group, converting one X, R¹ or R² group to another X, R¹ orR² group, converting a salt product to the free base or anotherpharmaceutically acceptable salt, or converting a free base product to apharmaceutically acceptable salt.

Conventional conditions for condensation of amines with carboxylic acidsor active derivatives thereof, such as acid chlorides, may be used. Forexample the amides and acids may be reacted in the presence of a mixtureof ethyl(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in asuitable solvent such as dimethyl formamide, and amines and acidchlorides may be reacted together in a suitable solvent such as ethylacetate or dichloromethane, optionally in the presence of a base such astriethylamine.

Reaction of a compound of formula (III) which is an acid chloride (Y═Cl)typically results in formation of the hydrochloride salt of the compoundof formula (I). Hydrochloride salts can also be obtained by passing HClgas into a solution of the free base, or adding a solution of HCl inether.

Conversions of an R^(1A) or R^(2A) group to a R¹ or R² group typicallyarise when a protecting group is needed during the above couplingreaction or during the preparation of the reactants by the proceduresdescribed below. Interconversion of one R¹ or R² group to anothertypically arises when one compound of formula (I) is used as theimmediate precursor of another compound of formula (I) or when it iseasier to introduce a more complex or reactive substituent at the end ofa synthetic sequence.

Compounds of formula (II) may be prepared from anitro-tetrahydroisoquinoline of formula (IV).

by reaction with a compound R^(1A)Z where Z is a leaving group such ashalogen, especially iodo, or tosylate to obtain an intermediate offormula (V)

which can be hydrogenated, for example using either tin (II) chlorideand HCL or hydrogen and a palladium/activated carbon catalyst, to obtainan amino-tetrahydroisoquinoline of formula (II).

When the intended R^(1A) group is methyl, the compound of formula (IV)may also be reacted with formic acid and formaldehyde to introduce theN-methyl group.

The nitro-tetrahydroisoquinoline of formula (IV) in which X^(A) ishydrogen may be prepared by hydrolysis of2-trifluoroacetyl-7-nitro-tetrahydroisoquinoline obtained by reaction ofan N-(nitrophenyl)ethyl-trifluoroacetamide and paraformaldehyde inacidic conditions using the procedure of Stokker, Tet. Lett., 1996, 37,5453. N-(nitrophenyl)ethyl-trifluoroacetamides can be prepared fromreadily available materials by reaction of trifluoracetic anhydride withlutidine and nitrophenethylamine hydrochloride, as illustrated in theDescriptions below.

Compounds of formula (II) may also be prepared from the correspondingamino-isoquinoline (or its nitro-analogue) of formula (VI)

where R^(N) is NH₂ or NO₂

by reaction with a compound R^(1A)Z where Z is a leaving group such ashalogen, especially iodo, or tosylate to obtain an intermediate offormula (VII)

which can be reduced, for example using sodium borohydride, orhydrogenated, for example using hydrogen and a palladium/activatedcarbon catalyst, to obtain a tetrahydroisoquinoline of formula (It).When the compound of formula (VII) is replaced by a nitro-isoquinoline,the nitro group is converted to an amino group in the hydrogenationstep.

When the intended R¹ is hydrogen, the N of the tetrahydroisoquinoline orisoquinoline is preferably protected conventionally, prior to thecoupling step that forms the carboxamide of formula (I), for example bytert.-butoxycarbonyl or trifluoroacetyl. The compound can be deprotectedunder standard conditions, for example using trifluoroaceticacid/methylene chloride or potassium carbonate in aqueous methanol.

Amino/nitro-isoquinolines of formulae (VI) and the reagents used arecommercially available, or can be prepared from commercially availablematerials using conventional procedures described in the literature.

The substituent X^(A) may be a group X already present on commerciallyavailable starting materials usable in the above described procedures.When the substituent X^(A) is a group convertible to X, then X may beintroduced during any of the procedures above, for example byconventional substitution of the aromatic ring of compounds of formula(IV), (V) or (VII). Most suitably the substituent X as halogen isintroduced to a compound of formula (II) in which X^(A) is hydrogen. Forexample, X as halogen may be incorporated by reaction with ahalo-succinimide as illustrated in the Descriptions below. As a furtherexample, X as alkyl may be introduced by reaction of a compound offormula (II) in which X is bromo with an alkyl stannane, as illustratedin the Descriptions and Examples below. The compound of formula (II) inwhich X is bromo may be obtained by halogenation of anamino-tetrahydroisoquinoline of formula (II) in which X^(A) is hydrogenwith NBS, again using procedures illustrated in the Descriptions below.

Compounds of formula (III) may be prepared by further substitution ofcommercially available benzoic acid or thiophene carboxylic acidderivatives using conventional procedures, or by oxidation ofcorresponding substituted benzyl alcohols. Alternatively benzoic acidscan be prepared from correspondingly substituted phenols, for example byformation of the acetate, conversion to an acetophenone and then to thedesired acid. Examples of these procedures are documented in WO 98/41507and WO98/41508.

Where the above described intermediates are novel compounds, they alsoform part of this invention.

The preparation of compounds of this invention is further illustrated bythe following Descriptions and Examples. The utility of compounds ofthis invention is shown by the Pharmacological Data that follow theExamples.

Description 1

N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide

A solution of trifluoroacetic anhydride (10.6 ml) in dichloromethane(100 ml) was added dropwise to a stirred solution of 2,6-lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2 g; 75 mmol) at 0° C.The mixture was stirred at 25° C. overnight under argon and then washedwith dilute citric acid (×2), brine and dried over Na₂SO₄. The materialin the organic phase gave the tide compound D1 as a pale yellow solid(19.04 g).

Description 2

7-Nitro-1,2,3,4-tetrahydro-2-trifluoracetylisoquinoline

The compound D1 (2.26 g; 9.15 mmol) and paraformaldehyde (0.45 g; 14.4mmol) in acetic acid (10 ml) and conc. H₂SO₄ (15 ml) were stirred at 25°C. for 20 h according to the procedure of G. E. Stokker., Tet. Lett.,1996, 37, 5453. Work up afforded the title compound D2 as a white solid(2.17 g).

¹H NMR (CDCl₃) δ: 3.10 (2H, m), 3.92 (2H, m), 4.85+4.92 (2H, 2×s), 7.38(1H, t), 8.10 (2H, m); m/z (EI): 274 (M⁺)

Description 3

7-Nitro-1,2,3,4-tetrahydroisoquinoline

The compound D2 (17.22 g; 63 mmol) was hydrolysed at room temperatureusing a solution of potassium carbonate (46.6 g) in 10% aqueous methanol(660 ml). Work-up with dichloromethane gave the title compound (11 g).

Description 3

7-Amino-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline

The 7-nitro compound D2 (0.99 g; 3.6 mmol) in ethanol (50 ml) washydrogenated over 10% palladium on carbon (450 mg) at atmosphericpressure for 4 h. The catalyst was removed by filtration through a padof Celite and evaporation in vacuo gave the title compound as a whitesolid (840 mg).

¹H NMR (250 MHz, CDCl₃) δ: 2.84 (2H, t), 3.23 (2H, br s), 3.82 (2H, m),4.66 (2H, d, restricted rotation around C−1), 6.47 (1H, m), 6.57 (1H,m), 6.96 (1H, m)

Description 4

7-Amino-8-chloro-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline

To a solution of amine D3 (1.00 g) in acetonitrile (20 ml)N-chlorosuccinimide (0.60 g) was added and the solution stirred at roomtemperature for 6 days. The solution was diluted with ethyl acetate,washed with water and the organic phase dried (MgSO₄) and solventremoved at reduced pressure. The residue was column chromatographed(silica gel, dichloromethane then 2% methanol/dichloromethane) to give7-amino-8-chloro-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinoline (0.72g) as a pale yellow solid.

¹H NMR (250 MHz, CDCl₃) δ: 2.85 (2H, m), 3.83 (2H, dt, restricted amiderotation), 4.76 (2H, s), 6.68 (1H, m) and 6.89 (1H, m).

Description 5

7-Amino-8-bromo-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinoline

The title compound (0.27 g) was prepared from amine D3 (0.24 g) andN-bromosuccinimide (0.20 g) according to the method of Description 4.

¹H NMR (250 MHz, CDCl₃) δ: 2.85 (2H, m), 3.76-3.87 (2H, m, restrictedamide rotation), 4.72 (2H, d due to restricted amide rotation), 6.68(1H, m) and 6.93 (1H, m).

Preparation 1

3-Bromo-4-ethoxybenzoic acid

To a solution of 4ethoxybenzoic acid (3.6 g, 0.022 mol) in chloroform(60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform (20 ml)dropwise. After stirring overnight at room temperature the precipitatewas filtered off and dried to afford the title compound as a whitesolid.

¹H NMR (DMSO-D₆) δ: 1.45 (3H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 7.26(1H, d, J=9 Hz), 7.98 (1H, dd, J=2, 9 Hz), 8.12 (1H, d, J=2 Hz)

Preparation 2

4-Methoxy-3-trifluoromethylbenzoic acid

3-Bromo-4-ethoxybenzoic acid methyl ester (1.4 g; 5.4 mmol) in DMF (25ml) and toluene (8 ml) under argon was treated with potassiumtrifluoroacetate (1.53 g; 10.1 mmol) and copper (I) iodide (2.1 g, 10.9mmol). The mixture was heated to 170° C. with removal of water(Dean/Stark), and then at 155° C. overnight. The mixture was allowed tocool, poured into ether and water and filtered through Kieselguhr. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to give abrown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave asolid which was hydrolysed in 1:1 methanolic: aqueous NaOH 50 ml) at 50°C. Work-up gave the title compound as a white solid (1 g).

¹H NMR (DMSO-D₆) δ: 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90 (1H, d, J=2Hz), 8.00 (1H, dd, J=2, 9 Hz), 12.70-13.10 (1H, br, exchangeable)

Preparation 3

4-Methoxy-3-trifluoromethylbenzoyl chloride

The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoicacid with oxalyl chloride and DMF in chloroform at room temperature [D.Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.

Preparation 4

3-Chloro-4-ethoxybenzoic acid

¹H NMR (DMSO-D₆) δ: 1.39 (3H, t, J=7 Hz), 4.20 (2H, q, J=7 Hz), 7.22(1H, d, J=7 Hz), 7.87 (2H, m).

Preparation 5

Methyl 3-Bromo-4-iso-propoxybenzoate

Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) wastreated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane(2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up withethyl acetate gave the title compound (3.0 g).

¹H NMR (250 MHz, CDCl₃) δ: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H,m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8, 2 Hz), 8.22 (1H, d, J=2 Hz)

Preparation 6

Methyl 3-Acetyl-4-iso-propoxybenzoate

The bromo ester P5 (2.5 g, 8.3 mmol) in dry dioxan (30 ml) was treatedwith (1-ethoxyvinyl)-tributyl tin (3.58 g, 9.9 mmol) followed bytetrakis triphenylphosphine palladium(o) (0.48 g, 0.4 mmol) and heatedat 100° for 18 h. After cooling, the mixture was acidified and aqueouswork-up and extraction into ethyl acetate gave a coloured oil (5.6 g).Flash chromatography on Kieselgel 60 [hexane to 20% EtAc/hexane gave thetitle compound as a yellow oil (2.3 g).

Preparation 7

3-Acetyl-4-iso-propoxybenzoic acid

Saponification of the ester P6 (2.3 g) gave the title compound as awhite solid (1.3 g).

¹H NMR (250 MHz, CDCl₃) δ: 1.48 (6H, d, J=7 Hz), 2.63 (3H, s), 4.80 (1H,m), 7.00 (1H, d, J=8 Hz), 8.17 (1H, dd, J=8, 2 Hz), 8.46 (1H, d, J=2 Hz)

Preparation 8

3-Acetyl-4-ethoxybenzoic acid

Prepared in a similar maimer to that described for Preparations 6 and 7.

¹H NMR (250 MHz, CDCl₃) δ: 1.53 (3H, t, J=7 Hz), 2.65 (3H, s), 4.23 (2H,q, J=7 Hz), 7.01 (1H, d, J=8 Hz), 8.19 (1H, dd, J=8, 2 Hz), 8.48 (1H, d,J=2 Hz).

EXAMPLE 1

N-(8-Chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

To a solution of amine D4 (0.28 g) in tetrahydrofuran (5 ml) containingtriethylamine (0.21 ml), 3-bromo-4-ethoxybenzoyl chloride (0.37 g) intetrahydrofuran (7 ml) was added. The mixture was stirred overnightpartitioned between ethyl acetate and water and the organic phase dried(MgSO₄) and solvent removed at reduced pressure. The residue waspurified by column chromatography (silica gel, and an ethylacetate/hexane gradient to give after combining of appropriate fractionsthe title compound (0.31 g) as a colourless solid.

¹H NMR (250 MHz, CDCl₃) δ: 1.26 (3H, t), 2.98 (2H, m), 3.85 (2H, dt,restricted amide rotation), 4.11 (2H, q), 4.80 (2H, d due to restrictedamide rotation) 6.98 (1H, d), 7.18 (1H, t), 7.84 (1H, dd), 8.14 (1H, d),8.28 (1H, m) and 8.39 (1H, d); m/z (API): 507 (MH⁺; 100%)

EXAMPLE 2

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

A solution ofN-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide(0.28 g) in methanol/water (5 ml 9:1) was treated with potassiumcarbonate (0.38 g) and stirred 12 h. The mixture was diluted withdichloromethane and washed with water. The organic phase was dried(MgSO₄) solvent removed at reduced pressure. The residue waschromatographed (silica gel, dichloromethane/methanol/ammonia up to9:1:0.1 eluant) to give the title compound (0.18 g) as a colourlesssolid.

¹H NMR (250 MHz, CDCl₃) δ: 1.52 (3H, t), 2.79 (2H, t), 3.11 (2H, t),4.04 (2H, s) 4.20 (2H, q) 6.96 (1H, d, J=6 Hz), 7.09 (1H, d, J=8.5 Hz),7.84 (1H, dd, J=8.5, 2 Hz), 8.13 (1H, d, J=2 Hz), 8.26-8.29 (2H, m); m/z(API): 409, 411 (MH⁺; 100%)

EXAMPLE 3

N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide

A solution ofN-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide(0.12 g) in 37% aqueous formaldehyde (0.63 ml) and formic acid (0.34 ml)and stirred at 80° C. for 3 h. Solid sodium hydroxide was added toneutralise the solution and the aqueous phase extracted withdichloromethane. The combined organic extracts were dried (MgSO₄) andsolvent removed in vacuo to give the title compound (0.11 g).

¹H NMR (250 MHz, CDCl₃) δ: 1.52 (3H, t), 2.52 (3H, s), 2.68 (2H, t),2.93 (2H, t), 3.61 (2H, s), 4.18 (2H, q), 6.96 (1H, d, J=6 Hz), 7.10(1H, d, J=8.5 Hz), 7.84 (1H, dd, J=8.5, 2 Hz), 8.13 (1H, d, J=2 Hz),8.25-8.28 (2H, m); m/z (API): 423, 425 (MH⁺; 100%)

EXAMPLE 4

N-(8-Chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.32 g) was prepared from amine D4 (0.28 g) and4-methoxy-3-trifluoromethylbenzoyl chloride (0.33 g) according to theprocedure of Example 1.

¹H NMR (250 MHz, CDCl₃) δ: 2.99 (2H, m), 3.85 (2H, dt, restricted amiderotation), 4.81 (2H, d due to restricted amide rotation) 7.12-7.21 (2H,m), 8.08 (1H, d), 8.16 (1H, s), 8.28-8.40 (2H, m); m/z (API): 481 (MH⁺;100%)

EXAMPLE 5

N-(8-Chloro-1,2,3,4-tetrahydroquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.05 g) was prepared fromN-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3methoxy-3-tifluoromethylbenzamide(0.29 g) according to the procedure of Example 2.

¹H NMR (250 MHz, CDCl₃) δ: 2.79 (2H, t), 3.11 (2H, t), 4.00 (3H, s),4.05 (2H, s), 7.11 (2H, t), 8.09 (1H, d), 8.16 (1H, s), 8.26 (1H, d) and8.31 (1H, br. s); m/z (API): 385 (MH⁺; 100%)

EXAMPLE 6

N-(8-Chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.13 g) was prepared fromN-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.19 g) according to the procedure of Example 3.

¹H NMR (250 MHz, CDCl₃) δ: 2.53 (3H, s), 2.68 (2H, t), 2.92 (2H, t),3.61 (2H, s) 4.00 (3H, s), 7.12 (2H, d), 8.09 (1H, d), 8.15 (1H, s),8.26 (1H, d) and 8.29 (1H, br. s); m/z (API): 385 (MH⁺; 100%)

EXAMPLE 7

N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.32 g) was prepared from amine D5 (0.22 g) and4methoxy-3-trifluoromethylbenzoyl chloride (0.22 g) according to theprocedure of Example 1.

¹H NMR (250 MHz, CDCl₃) δ: 2.94-3.01 (21, m), 3.82-3.93 (2H, m,restricted amide rotation), 4.01 (3H, s), 4.78 (2H, d due to restrictedamide rotation) 6.95 (1H, d), 7.14 (1H, d), 8.04 (1H, d), 8.18 (1H, s),8.36 (1H, d) and 8.39 (1H, s); m/z (API): 524, 526 (MH⁺; 100%).

EXAMPLE 8

N-(8-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.12 g) was prepared fromN-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide(0.24 g) according to the procedure of Example 2.

¹ H NMR (250 MHz, CDCl₃) δ: 2.79 (2H, t), 3.11 (2H, t), 4.00 (5H, s),7.13 (2H, dd), 8.10 (1H, dd, J=2.3 and 8.7 Hz) 8.18 (1H, d, 32.1 Hz),8.25 (1H, d, J=8.5 Hz) and 8.38 (1H, s); m/z (API): 429, 431 (MH⁺; 100%)

EXAMPLE 9

N-(8-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.08 g) was prepared fromN-(8-bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.09 g) according to the procedure of Example 3.

¹H NMR (250 MHz, CDCl₃) δ: 2.53 (3H, s), 2.67 (2H, t), 2.94 (2H, t),3.59 (2H, s), 4.00 (3H, s), 7.15 (2H, t), 8.11 (1H, dd) 8.18 (1H, d),8.25 (1H, d, J=8.5 Hz) and 8.37 (1H, s); m/z (API): 443, 445 (MH⁺; 100%)

EXAMPLE 10

N-2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

a)N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxy-3-trifluoromethylbenzamide(0.25 g), was combined with lithium chloride (0.06 g), tetramethyltin(0.08 ml) and bis(triphenylphosphine)palladium(II)chloride (0.025 g) indimethylformamide (5 ml) and the mixture warmed to 100° C. for 24 h.Solvent was removed at reduced pressure, filtered (Celite pad) and thefiltrate column chromatographed (silica gel, diethyl ether eluant) togiveN-(8-methyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide(0.16 g).

¹H NMR (CDCl₃) δ: 2.31 (3H, m), 2.95-2.99 (2H, m), 3.81-3.90 (2H, m),4.07 (3H, s), 4.70, 4.73 (2H, s, appears as 2 singlets due to restrictedrotation), 7.04-7.12 (2H, m), 7.41-7.47 (1H, m), 7.63 (1H, br. s.),8.08-8.11 (2H, m); m/z (API⁺): 461 (MH⁺)

b)N-(8-Methyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.15 g) in methanol: 2N sodium hydroxide (15 ml 2:1) was stirred atroom temperature for 1 h. 2M hydrochloric acid (4.5 ml) was added andsolvent (10 ml) removed at reduced pressure. The residual solvent wasextracted with dichloromethane, the organic phase washed with brine,dried MgSO₄) and solvent removed at reduced pressure to giveN-(8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.08 g)

¹H NMR (CDCl₃) δ: 2.31 (3H, m), 2.07 (3H, s), 2.80 (2H, t), 3.09 (2H,t), 3.95 (2H, s), 3.98 (3H, s), 6.98 (1H, d), 7.09 (1H, d), 7.32 (1H,s), 7.69 (1H, br. s.), 8.07-8.10 (2H, m); m/z (API⁺): 365 (MH⁺)

c) The title compound (0.03 g) was prepared fromN-(8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide(0.08 g), according to the method of Example 3.

¹H NMR (CDCl₃) δ: 2.01 (3H, s), 2.48 (3H, s), 2.68 (2H, t), 2.95 (2H,t), 3.48 (2H, s), 3.99 (3H, s), 7.00 (1H, d), 7.09 (1H, d), 7.30 (1H,d), 7.92 (1H br. s.), 8.08 (1H, br. s.), 8.11 (1H, br. s.); m/z (API⁺):379 (MH⁺)

EXAMPLE 11

N-(2-(2-Hydroxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

a) A mixture ofN-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.192 g) and 2-bromoethoxy-tert-butyldimethylsilane (0.24 g) werecombined in dimethylformamide and warmed to 80° C. for 18 h. Solvent wasremoved at reduced pressure, the residue dissolved in dichloromethaneand washed with saturated sodium hydrogen carbonate. The organic phasewas dried (MgSO₄) and solvent removed at reduced pressure. The residuewas column chromatographed (silica gel, ammonia/methanol/dichloromethanemixtures as eluant) to giveN-(2-(2-tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.09 g)

b)N-(2-(2-Tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.09 g) in tetrahydrofuran (10 ml) was treated with tetrabutylammoniumfluoride in tetrahydrofuran (1M, 0.16 ml) at room temperature overnight.The reaction mixture was diluted with ethyl acetate, washed with water,the organic phase dried (MgSO₄) and solvent removed at reduced pressure.The residue was column chromatographed (silica gel,ammonia/methanol/dichloromethane mixtures as eluant) to give the titlecompound (0.04 g)

¹H NMR CDCl₃) δ: 2.80 (4H, m), 2.91 (2H, m), 3.73 (2H, s), 3.75 (2H, t),3.99 (3H, s), 7.11 (2H, dd), 8.07 (1H, dd), 8.16 (1H, d), 8.25 (1H, d)and 8.32 (1H, br. s.); m/z (API⁺): 429 (MH⁺)

EXAMPLE 12

N-(2-Formyl-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

Formic acetic anhydride (0.21 g) was added toN-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.15 g) and dimethylaminopyridine (0.05 g) in dichloromethane. Themixture was stirred at room temperature overnight and quenched withsaturated aqueous sodium hydrogen carbonate (20 ml). The organic phasewas separated and washed with brine, dried (MgSO₄) and solvent removedat reduced pressure. The residue was column chromatographed (silica gel,ammonia/methanol/dichloromethane mixtures as eluant) to give the titlecompound (0.10 g)

¹H NMR (d⁶-DMSO, 353° K.) δ: 3.79 and 2.90 (21I, t, rotamers), 3.68 (2H,m), 3.99 (3H, s), 4.55 and 4.62 (2H, s, rotamers), 7.23 (1H, d), 7.39(1H, d), 7.44 (1H, d), 8.21, 8.27, 8.32 (3H, s), 10.20 (1H, s); m/z(API⁺): 413 (MH⁺)

EXAMPLE 13

N-(8-Ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.525 g), lithium chloride (0.127 g), tetraethyltin (0.47 g) andbis(triphenylphosphine)palladium(II)chloride (0.04 g) were combined indimethylformamide (10 ml) and the mixture stirred under argon at 120° C.for 20 h. Solvent as removed at reduced pressure, the residue dissolvedin dichloromethane and filtered through Celite. Solvent was removed atreduced pressure and the residue column chromatographed (silica gel,ethyl acetate/hexane mixtures) to give the title compound (0.18 g) as anoil.

¹H NMR (CDCl₃) δ: 1.24 (3H, t), 2.66 (21, m), 2.99 (2H, m), 3.84 (2H,m), 4.00 (3H, s), 4.77 and 4.82 (2H, s, rotamers), 7.10 (2H, m), 7.62(2H, m), 8.08 (2H, m); m/z (API⁺): 475 (MH⁺)

EXAMPLE 14

N-(8-Ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide(0.157 g) was dissolved in methanol/water (5:1 6 ml), potassiumcarbonate (0.228 g) added and the mixture stirred overnight. The mixturewas partitioned between dichloromethane and water the organic phaseseparated and solvent removed at reduced pressure. The residue wascolumn chromatographed (silica gel, ammonia/methanol/dichloromethanemixtures as eluant) to give the title compound (0.97 g)

¹H NMR (CDCl₃) δ: 1.15 (3H, t), 2.57 (2H, q), 2.82 (2H, t), 3.10 (2H,t), 3.99 (3H, s), 4.04 (2H, s), 7.00 (1H, d), 7.10 (1H, d), 7.49 (1H,d), 7.62 (1H, br. s.), 8.05-8.10 (2H, m); m/z (API⁺): 379 (NM⁺)

EXAMPLE 15

N-(8-Ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.08 g) was prepared fromN-(8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.08 g) according to the method of Example 3.

¹H NMR (CDCl₃) δ: 1.17 (3H, t), 2.56 (3H, s), 2.57 (2H, q), 2.68 (2H,t), 2.95 (2H, m), 3.61 (2H, s), 3.99 (3H, s), 7.04 (1h, d), 7.10 (1H,d), 7.51 (1H, d), 7.59 (1H, s), 8.04-8.09 (2H, m); m/z (API⁺): 393 (MH⁺)

EXAMPLE 16

N-(8-Chloro-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.193 g) in dichloromethane (10 ml) containing triethylamine (0.055 ml)was treated with methanesulfonyl chloride ((0.063 g) and the mixturestirred for 48 h. Water was added and the organic phase separated andsolvent removed at reduced pressure. The residue was triturated withdiethyl ether to give the title compound (0.19 g).

¹H NMR (CDCl₃) δ: 2.91 (3H, s), 3.00 (2H, t), 3.56 (2H, t), 4.01 (3H,s), 4.48 (2H, s), 7.13 (1H, d), 7.23 (1H, d), 8.08 (1H, dd), 8.16 (1H,s), 8.29 (1H, s), 8.35 (1H, d); m/z (API⁺): 463 (MH⁺)

EXAMPLE 17

N-(8-Styryl-2-trifluroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

A mixture ofN-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.525 g), palladium diacetate (0.011 g), tris(o-tolyl)phosphine (0.03g), triethylamine (0.15 g) and styrene (0.16 g) were combined inacetonitrile and warmed to reflux for 23 h. The mixture was cooled,partitioned between dichloromethane/water, the organic phase separatedand solvent removed at reduced pressure. The residue was columnchromatographed (silica gel, ethyl acetate/hexane mixtures as eluant) toprovide the title compound (0.46 g).

¹H NMR (CDCl₃) δ: 2.99 (2H, m), 3.85 (2H, m), 3.93, 4.01 (3H, s,rotamers), 4.75 (2H, m), 6.81-7.26 (4H, m), 7.39-7.53 (3H, m), 7.92-8.40(4H, m); m/z (API⁺): 549 (MH⁺)

EXAMPLE 18

N-(8-Styryl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide

The title compound (0.08 g) was prepared fromN-(8-styryl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.439 g) according to the method of Example 2.

¹H NMR (CDCl₃) δ: 2.83 (2H, t), 3.12 (2H, t), 3.93 (3H, s), 3.99 (2H,s), 6.77 (1H, d), 6.94 (1H, d), 7.00 (1H, s), 7.11 (1H, d), 7.30-7.50(5H, m), 7.93-7.99 (2H, m), 8.16 (1H, d), 8.26 (1H, s); m/z (API⁺): 453(MH⁺)

EXAMPLE 19

N-(8-Styryl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamidehydrochloride

The title compound (0.033 g) was prepared fromN-(8-styryl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide(0.068 g) according to the method of Example 3. The free base wasconverted into the hydrochloride salt by treatment of a methanolsolution with excess ethereal HCl.

¹H NMR (CDCl₃) δ: 2.46 (3H, s), 2.66 (2H, t), 2.95 (2H, t), 3.52 (2H,s), 3.93 (3H, s), 6.79 (1H, d), 6.95 (1H, d), 7.00 (1H, s), 7.14 (1H,d), 7.35-7.53 (5H, m), 7.93-7.98 (2H, m), 8.20 (1H, d), 8.25 (1H, s);m/z (API⁺): 467 (MH⁺)

The following Examples were prepared using the methods described for theDescriptions, Preparations and Examples above.

EXAMPLE 20

N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 1.54 (3H, t, J=7 Hz), 2.68 (3H, s), 2.98(21H, m), 3.87 (2H, m, restricted amide rotation), 4.25 (2H, q, J=7 Hz),4.80 (2H, br) 7.05 (1H, d, J=8 Hz), 7.19 (1H, m), 8.04 (1H, d), 8.10(1H, dd, J=8, 2 Hz), 8.22-8.36(2H, m) and 8.32 (1H, m); m/z (API): 537,535 (MNa⁺; 100%), 515, 513 (MH⁺; 10%).

EXAMPLE 21

N-(8-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

¹H NMR (250 MHz, d₆DMSO) δ: 1.46 (3H, t, J=7 Hz), 2.60 (3H, s), 2.73(2H, t), 2.93 (2H, t), 3.82 (2H, s), 4.26 (2H, q, J=7 Hz), 7.12 (1H, d,J=8 Hz), 7.28 (2H, m), 8.15 (1H, dd, J=8, 2 Hz), 8.26 (2H, s), 9.95 (1H,s); m/z (API): 419, 417 (MH⁺; 100%)

EXAMPLE 22

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 2.79 (2H, t,), 3.11 (2H, t), 3.97 (3H, s),4.05 (2H, s), 7.09 (2H, m), 7.68 (2H, m), 8.28 (2H, m); m/z (API): 335.1(MH⁺; 100%)

EXAMPLE 23

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 1.51 (3H, t, J=7 Hz), 2.78 (2H, t,), 3.10(2H, t), 4.03 (2H, s), 4.18 (2H, q, J=7 Hz), 6.98 (1H, d, J=8 Hz), 7.06(1H, d), 7.77 (1H, dd, J=8, 2 Hz), 7.94 (1H, d), 8.23 (1H, d), 8.31 (1H,s); m/z (API): 365.1 (MH⁺; 100%)

EXAMPLE 24

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide

¹H NMR (250 MHz, d₆DMSO) δ: 2.70 (2H, t), 2.91 (2H, t), 3.83 (21, s),3.94 (3H, s), 7.10 (1H, d, J=8 Hz), 7.22-7.32 (2H, m), 8.02 (1H, dd,J=8, 2 Hz), 8.22 (1H, d, J=2 Hz), 9.98 (1H, s); m/z (API): 397, 395(MH⁺; 100%)

EXAMPLE 25

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 1.54 (3H, t, J=7 Hz), 2.68 (3H, s), 2.80 (2H,t), 3.12 (2H, t), 4.05 (2H, s), 4.24 (2H, q, J=7 Hz), 7.07 (2H, m), 8.11(1H, dd, J=8, 2 Hz), 8.25 (2H, m), 8.37 (1H, s); m/z (API): 373.2 (MH⁺;100%)

EXAMPLE 26

N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide

¹H NMR (250 MHz, CDCl₃) δ: 1.46 (6H, d, J=7 Hz), 2.66 (3H, s), 2.78 (2H,t), 3.10 (2H, t), 4.04 (2H, s), 4.80 (1H, sep, J=7 Hz), 7.07 (2H, d, J=8Hz), 8.10 (1H, dd, J=8, 2 Hz), 8.21 (1H, d, J=8 Hz), 8.24 (1H, d, J=2Hz), 8.39 (1H, s); m/z (API): 409 (MNa⁺; 100%), 387 (MH⁺; 18%)

PHARMACOLOGICAL DATA

1. Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity, including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol(hereinafter referred to as Compound A). It has been found that thecompounds of WO 92/22293 bind to a novel receptor obtainable from ratforebrain tissue, as described in WO 96/18650 (SmithKline Beecham). Theaffinity of test compounds to the novel receptor site is assessed asfollows.

Method

Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mM Tris/HCl, pH 7.4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at −70° C. until used.

To carry out the radioligand binding assay, aliquots of tissue preparedas above (usually at a concentration of 1-2 mg protein/ml) are mixedwith aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. [3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Whatman GF/B glass fibre filters. The filters arethen washed rapidly with ice-cold buffer. The amount of radioactivitybound to the tissue trapped on the filters is measured by addition ofliquid scintillation cocktail to the filters followed by counting in aliquid scintillation counter.

In order to determine the amount of “specific” binding of [3H]-CompoundA, parallel assays are carried out as above in which [3H]-Compound A andtissue are incubated together in the presence of unlabelled Compound A(usually 3 μM). The amount of binding of [3H]-Compound A remaining inthe presence of this unlabelled compound is defined as “non-specific”binding. This amount is subtracted from the total amount of[3H]-Compound A binding (i.e. that present in the absence of unlabelledcompound) to obtain the amount of “specific” binding of [3H]-Compound Ato the novel site.

The affinity of the binding of test compounds to the novel site can beestimated by incubating together [3H]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H]-Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted graphically, and non-linear regression analysis of the resultantcurve is used to provide an estimate of compound affinity in terms ofpKi value.

Results

Compounds of this invention were active in this test with pKi's greaterthan 6. For example, compounds of Examples 2, 3, 5, 6, 8-12, 14, 15, 18,19 gave pKi values greater than 7.

2. MEST Test

The maximal electroshock seizure (MEST) threshold test in rodents isparticularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

Method for mouse model

Mice (naive male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec, 50 Hz, sine wave form) administered viacorneal electrodes. The mean current and standard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the ‘up and down’ method of Dixon andMood (1948)². Statistical comparisons between vehicle- and drug-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

2. Dixon, W. J. and Mood, A. M. (1948). J. Amer. Stat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F. (1949). J. Pharmacol. exp. Ther.,96, 99-113

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

Studies are carried out using a Hugo Sachs Electronik Constant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Results

Compounds of this invention dosed at 10 mg/kg by the oral route as asuspension in methyl cellulose and tested one hour post dosing showed anincrease in seizure threshold.

Method for rat model

The threshold for maximal (tonic hindlimb extension) electroshockseizures in male rats (Sprague Dawley, 80-150 g, 6 weeks old) wasdetermined by a Hugo Sachs Electronik stimulator which delivered aconstant current (0.3 sec duration; from 1-300 mA in steps of 5-20 mA).The procedure is similar to that outlined above for mouse and fulldetails are as published by Upton et al,.⁴

4. N. Upton, T. P. Blackburn, C. A. Campbell, D. Cooper, M. L. Evans, H.J. Herdon, P. D. King, A. M. Ray, T. O. Stean, W. N. Chan, J. M. Evansand M. Thompson. (1997). B. J. Pharmacol., 121, 1679-1686

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated.

Drugs are suspended in 1% methyl cellulose.

Results

At a dosage of 2 mg/kg p.o. at 2 h, the compounds of Examples 2, 3, 5,6, 8 and 9 show statistically significant increases of 120%, 160%, 320%,260%, 400% and 340% respectively.

What is claimed is:
 1. A compound of formula (I) or pharmaceuticallyacceptable salt or solvate thereof:

where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R¹ ishydrogen, C₁₋₆alkyl (optionally substituted by hydroxy or C₁₋₄alkoxy),C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkylCO—, formyl, CF₃CO— or C₁₋₆alkylSO₂—,R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, CF₃O, CF₃S—, CF₃CO—, tifluoromethyldiazirinyl, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆perfluoroalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkylO—, C₁₋₆alkylCO—, C₃₋₆cycloalkylO—,C₃₋₆cycloalkylCO—, C₃₋₆cycloalkyl-C₁₋₄alkylO—,C₃₋₆cycloalkyl-C₁₋₄alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄alkyl-, C₁₋₆alkylS—, C₁₋₆alkylSO₂—, (C₁₋₄alkyl)₂NSO₂—,(C₁₋₄alkyl)NHSO₂—, (C₁₋₄alkyl)₂NCO—, (C₁₋₄alkyl)NHCO, CONH₂, CF₃SO₂,C₁₋₆alkenyl, C₁₋₆alkynyl or C₁₋₆hydroxyalkyl; or —NR³R⁴ where R³ ishydrogen or C₁₋₄alkyl, and R⁴ is hydrogen, C₁₋₄alkyl, formyl,—CO₂C₁₋₄alkyl or —COC₁₋₄alkyl; or two R² groups together form acarbocyclic ring that is saturated or unsaturated and unsubstituted orsubstituted by —OH or ═O; and X is halogen, C₁₋₆alkoxy, C₁₋₆alkyl,C₂₋₆alkenyl optionally substituted by phenyl.
 2. A compound according toclaim 1 of formula (IA)


3. A compound according to claim 1 of formula (IB)


4. A compound of claim 1 in which R¹ is hydrogen, methyl, ethyl, propyl,hydroxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl, R² ishydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl, t-butyl,phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy,phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo,chloro, fluoro, iodo, acetyl, propionyl, pivaloyl, iso-butyroyl,benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy,trifluoroacetyl, trifluoromethyldiazirinyl, methanesulfonyl,n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl, CF₃SO₂; or twogroups R² form a benzene, cyclopentane or cyclopentanone ring; X ismethyl, ethyl, chloro, bromo, iodo, fluoro, phenylethenyl.
 5. A compoundof claim 1 in which R¹ is hydrogen, methyl, formyl, hydroxyethyl ortrifluoroacetyl, R² is hydrogen or one or more of methyl, ethyl,iso-propyl, methoxy, ethoxy, iso-propoxy, acetyl, propionyl, pivaloyl,cyano, bromo, chloro, fluoro, iodo, trifluoromethyl, X is methyl, ethyl,chloro or bromo.
 6. A compound of formula (I) of claim 1 selected from:N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;N-(8-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(2,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(2-(2-Hydroxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(2-formyl-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide;N-(8-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-chloro-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-Styryl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-Styryl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-Styryl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;N-(8-Bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxy-benzamide;N-(8-Bromo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide;N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide;N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide;N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide;andN-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide.7. A process for the preparation of compounds of formula (I) accordingto claim 1, which comprises reacting a compound of formula (II)

where R^(1A) is R¹ as defined in claim 1 or a group convertible to R¹and X^(A) is X as defined in claim 1 or a group convertible to X with acompound of formula (III)

where Q is as defined in formula (I), Y is Cl or OH, and R^(2A) groupsare independently R² as defined for formula (I) or groups convertible toR², and where required converting an X^(A), R^(1A) or R^(2A) group to anX, R¹ or R² group, converting one X, R¹ or R² group to another X, R¹ orR² group, converting a salt product to the free base or anotherpharmaceutically acceptable salt, or converting a free base product to apharmaceutically acceptable salt.
 8. A pharmaceutical compositionsuitable for use in the treatment and/or prophylaxis of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, oramyotrophic lateral sclerosis (ALS) which comprises a compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltor solvate thereof, and a pharmaceutically acceptable carrier.
 9. Amethod of treatment and/or prophylaxis of anxiety, mania, depression,panic disorders and/or aggression, disorders associated with asubarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from cocaine, nicotine, alcohol, benzodiazepines and othersubstances of abuse, epilepsy, post-traumatic epilepsy and otherdisorders treatable and/or preventable with anti-convulsive agents,Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease, Huntingdon's chorea, and other degenerativediseases, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, circadian rhythm disorders,insomnia, narcolepsy and other sleep disorders, Giles de la Tourette'ssyndrome and other tics, traumatic brain injury, tinnitus, neuralgia,trigeminal neuralgia, neuropathic pain, dental pain, cancer pain,inappropriate neuronal activity resulting in neurodysthesias, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, oramyotrophic lateral sclerosis (ALS) comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt or solvate thereof.
 10. A compound of claim 2 in whichR¹ is hydrogen, methyl, ethyl, propyl, hydroxyethyl, formyl, acetyl,trifluoroacetyl or methanesulfonyl, R² is hydrogen or one or more ofmethyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy, ethoxy,iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, amino,acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl,propionyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl,trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl,trifluoromethyldiazirinyl, methanesulfonyl, n-propylsulfonyl,isopropylsulfonyl, dimethylsulfamoyl, CF₃SO₂; or two groups R² form abenzene, cyclopentane or cyclopentanone ring; X is methyl, ethyl,chloro, bromo, iodo, fluoro, phenylethenyl.
 11. A compound of claim 3 inwhich R¹ is hydrogen, methyl, ethyl, propyl, hydroxyethyl, formyl,acetyl, trifluoroacetyl or methanesulfonyl, R² is hydrogen or one ormore of methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy,ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy,amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo,acetyl, propionyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl,trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl,trifluoromethyldiazirinyl, methanesulfonyl, n-propylsulfonyl,isopropylsulfonyl, dimethylsulfamoyl, CF₃SO₂; or two groups R² form abenzene, cyclopentane or cyclopentanone ring; X is methyl, ethyl,chloro, bromo, iodo, fluoro, phenylethenyl.
 12. A compound of claim 2 inwhich R¹ is hydrogen, methyl, formyl, hydroxyethyl or trifluoroacetyl,R² is hydrogen or one or more of methyl, ethyl, iso-propyl, methoxy,ethoxy, iso-propoxy, acetyl, propionyl, pivaloyl, cyano, bromo, chloro,fluoro, iodo, trifluoromethyl, X is methyl, ethyl, chloro or bromo. 13.A compound of claim 3 in which R¹ is hydrogen, methyl, formyl,hydroxyethyl or trifluoroacetyl, R² is hydrogen or one or more ofmethyl, ethyl, iso-propyl, methoxy, ethoxy, iso-propoxy, acetyl,propionyl, pivaloyl, cyano, bromo, chloro, fluoro, iodo,trifluoromethyl, X is methyl, ethyl, chloro or bromo.